Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

Fernando Chernomordik; Bojan Cercek; Jianchang Zhou; Xiaoning Zhao; Nicole Wai Man Lio; Kuang-Yuh Chyu; Prediman K Shah; Paul C Dimayuga

doi:10.3389/fimmu.2023.1113904

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

Front Immunol. 2023 Mar 27:14:1113904. doi: 10.3389/fimmu.2023.1113904. eCollection 2023.

Authors

Fernando Chernomordik¹, Bojan Cercek¹, Jianchang Zhou¹, Xiaoning Zhao¹, Nicole Wai Man Lio¹, Kuang-Yuh Chyu¹, Prediman K Shah¹, Paul C Dimayuga¹

Affiliation

¹ Oppenheimer Atherosclerosis Research Center, Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Abstract

Background: LL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.

Methods and results: The activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.

Conclusions: Our report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS.

Keywords: LL-37; T cells; acute coronary syndrome; immune checkpoint; platelets; self-antigen.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Coronary Syndrome* / metabolism
Autoantigens / metabolism
CD8-Positive T-Lymphocytes
CTLA-4 Antigen / metabolism
Humans
Leukocytes, Mononuclear

Substances

Autoantigens
CTLA-4 Antigen
CAMP protein, human

Grants and funding

The study was supported by The Heart Foundation, Eisner Foundation, Peterson Foundation, Spielberg Fund (PS). The Eleanor and Harold Foonberg Endowed Chair in Cardiac Intensive Care Fund (BC). Academic Affairs Department, Cedars Sinai Medical Center (FC). The Lydia Kitner Scholarship for Advanced Cardiovascular Training, the Milovicz grant for the Development of the Future Generation of Leaders in Medicine, and the Prof. Arieh Roth Scholarship from the Working Group in Acute Cardiac Care of the Israel Heart Society (FC).